Hypertension or abnormally high blood pressure is a growing public health concern for which successful treatment often remains elusive. Sixty-seven million Americans—about one-third of the adult population—have high blood pressure and these numbers are increasing as the population ages and obesity accelerates.
Hypertension is more common in men than women and afflicts approximately 50% of the population over the age of 65. Hypertension is serious because people with the condition have a higher risk for heart disease and other medical problems than people with normal blood pressure. If left untreated, hypertension can lead to arteriosclerosis, heart attack, stroke, enlarged heart and kidney damage.
Blood pressure is highest when the heart beats to push blood out into the arteries. When the heart relaxes to fill with blood again, the pressure is at its lowest point. Blood pressure when the heart beats is called systolic pressure. Blood pressure when the heart is at rest is called diastolic pressure. When blood pressure is measured, the systolic pressure is stated first and the diastolic pressure second. Blood pressure is measured in millimeters of mercury (mm Hg). For example, if a person's systolic pressure is 120 and diastolic pressure is 80, it is written as 120/80 mm Hg. Blood pressure lower than 120/80 mm Hg is considered normal.
A significant percentage of patients with uncontrolled hypertension fail to meet therapeutic targets despite taking multiple drug therapies at the highest tolerated doses, a phenomenon called resistant hypertension. This suggests there is an underlying pathophysiology resistant to current pharmacological approaches. Innovative therapeutic approaches are particularly relevant for these patients, as their condition puts them at high risk of major cardiovascular events.
The sympathetic nerve innervation of the kidney is implicated in the pathogenesis of hypertension through effects on rennin secretion, increased plasma rennin activity that leads to sodium and water retention, and reduction of renal (kidney) blood flow. As a result, a succession of therapeutic approaches has targeted the sympathetic nervous system to modulate hypertension, with varying success.
The sympathetic nerve innervation of the kidney is achieved through a dense network of postganglionic axons (nerves or nerve fibers) that innervate the kidney. This network of nerve fibers is often referred to as the renal plexus and runs alongside the renal artery and enters the hilum of the kidney. Thereafter, they divide into smaller nerve bundles following the blood vessels and penetrate cortical and juxtamedullary areas.
Preganglionic neuronal cell bodies are located in the intermediolateral cell column of the spinal cord. Preganglionic axons pass through the paravertebral ganglia (do not synapse) to become the lesser thoracic splanchnic nerve and least thoracic splanchnic nerve and travel to the aorticorenal ganglion which is located at the origin of the renal artery from the abdominal aorta. Postganglionic axons then enter the renal plexus, where they play an important role in the regulation of blood pressure by effecting renin release. The renal plexus contains only sympathetic components. There is no (or at least very minimal) parasympathetic innervation of the kidney.
As a result of the renal sympathetic nerves being implicated in the pathophysiology of systemic hypertension, a succession of therapeutic approaches has targeted the sympathetic nervous system to modulate hypertension, with varying success.
Surgical sympathectomy, the surgical cutting of a sympathetic nerve, was attempted more than 40 years ago in patients with malignant hypertension. Malignant hypertension was a devastating disease with a five-year mortality rate of almost 100%, thus interventional approaches have been tested for its treatment given the lack of effective drug therapy at the time. Sympathectomy was mainly applied in patients with severe or malignant hypertension, as well as patients with cardiovascular deterioration despite relatively good blood pressure reduction by other means.
Sympathectomy, also termed splanchnicectomy, was performed either in one or two stages, required a prolonged hospital stay (2-4 weeks) and a long recovery period (1-2 months) and importantly had to be performed by a highly skilled surgeon. It was thus performed only in a few select centers in the U.S. and Europe.
Sympathectomy proved to be effective in reducing blood pressure immediately postoperatively, and the results were maintained in the long term in most patients. Survival rates were also demonstrated to be high for patients undergoing the procedure. The two major limitations of splanchnicectomy were the required surgical expertise and the frequent adverse events occurring with this procedure. Adverse events were common and included orthostatic hypotension (very low blood pressure when standing up), orthostatic tachycardia, palpitations, breathlessness, anhidrosis (lack of sweating), cold hands, intestinal disturbances, sexual dysfunction, thoracic duct injuries and atelectasis (collapse of the lung).
After the introduction of antihypertensive drugs and due to its poor patient tolerance and surgical difficulty, sympathectomy was reserved for patients who failed to respond to antihypertensive therapy or could not tolerate it.
Recent studies have focused on using thermal energy delivered through a percutaneous approach to achieve renal nerve denervation. Renal denervation performed this way is designed to damage the renal nerve fibers along the length of the artery using thermal energy to block renal nerve activity, thus neutralize the effect of the renal sympathetic system which is involved in the development of hypertension. Percutaneous thermal device based renal nerve denervation may achieve such objectives, but is limited to appropriate renovascular anatomy. For example, patients diagnosed with renal arteriogram are excluded from treatment with the Simplicity™ Renal Denervation System (Medtronic, Minneapolis, Minn.) if renal artery diameter is less than 4 mm or renal artery length is less than 20 mm. Patients with accessory renal arteries, approximately 20-30% of the patient population, are also excluded from treatment.
Renal nerve denervation has also raised concerns of complications arising from significant amount of thermal endothelial damage required to create a complete renal nerve block along the length of the renal artery. Cases of renal artery stenosis after thermal renal nerve denervation have been reported in the literature.
As described above, the aorticorenal ganglion plays an import role in renal function including blood pressure regulation. Maillet (Innervation sympathique du rein: son role trophique. Acta Neuroveg., Part II, 20:337-371, 1960) describes various lesions of the renal parenchyma (functional tissue of the kidney, including the nephrons) after the chemical destruction of the aorticorenal ganglion in an animal model. Carbolic acid (5%) was brushed on the left aorticorenal ganglion or the left renal plexus. The renal parenchyma changes between the two techniques were shown to be identical.
Dolezel (Monoaminergic innervation of the kidney. Aorticorenal ganglion—a sympathetic, monoaminergic ganglion supplying the renal vessels. Experientia, 23:109-111, 1967) extirpated the left aorticorenal ganglion from 8 canines. 6-8 days later the left kidney was harvested and examined. Throughout the whole kidney the monoaminergic nerves terminating on the surface of the media of arteries, on the vasa recta, on the veins, in the fibrous skeleton of the kidney, and in the muscular part of the pelvic wall showed complete degeneration.
Norvell (Aorticorenal ganglion and its role in renal innervation. J. Comp. Neurol., 133:101-111, 1968) describes removing the aorticorenal ganglia from one side of 14 adult felines. Two weeks later, the kidneys were harvested and examined. Norvell observed that the large bundle of nerve fibers which are normally present in the perivascular connective tissue of the control kidney were found less frequently in the experimental kidneys. In the control kidneys, at least one, and sometimes several bundles of nerve fibers, was associated with any large blood vessel observed under the microscope. This was not the case in the experimental kidneys. It was difficult to find even a small bundle of nerve fibers in the area around the blood vessels. Fine nerve fibers going to the tubules were even more difficult to locate. Norvell concluded from the reduction of nerve fibers seen in the cat after removal of the aorticorenal ganglion, that this ganglion is important in both tubular and vascular innervation.
Various animal studies have shown that electrically stimulating renal nerves influences changes in renal hemodynamics such as renal blood flow (RBF) and glomerular filtration rate (GFR). From these animal studies emerged the concept of the graded response of the renal neuroeffectors to graded increase in the frequency of renal sympathetic nerve stimulation. At the lower frequency range (≈0.5 Hz), there is stimulation of renin secretion rate (RSR), without effects on urinary sodium excretion (UNAV), RBF or GFR. At slightly higher frequencies (≈1.0 Hz), there is both stimulation of RSR and a decrease in UNAV, without effects on RBF or GFR. At higher frequencies (≈2.0 Hz), there is stimulation of RSR and a decrease in UNAV and renal vasoconstriction, with decrease RBF (Gerald F. DiBona, Neural Control of the Kidney Past, Present and Future, Hypertension 2003; 41 [part 2]:621-624)
There is the need for a method and device that can regulate the innervation of the kidney to control diseases related to kidney function including hypertension without the limitations associated with only targeting renal nerve fibers with thermal energy.